Phragmunis a suppresses glioblastoma through the regulation of MCL1-FBXW7 by blocking ELK1-SRF complex-dependent transcription.

Glioblastoma (GBM) is a highly aggressive brain tumor. During screening work, we found a new compound named phragmunis A (PGA), which is derived from the fruitbody of Trogia venenata, exhibits a potential cytotoxic effect on patient-derived recurrent GBM cells and temozolomide (TMZ)-resistant cell lines. The present study was designed to investigate the potential molecular mechanism of the anti-glioma effects of PGA in vitro and in vivo. Studies investigating the mechanism revealed that PGA diminished the binding efficiency of ETS family of transcription factor (ELK1) and Serum response factor (SRF), and suppressed ELK1-SRF complex-dependent transcription, which decreased the transcriptional levels of downstream genes Early growth response protein 1 (EGR1)-Polycomb ring finger (BMI1), thus inducing the imbalanced regulation between Myeloid cell leukaemia-1 (MCL1) and F-Box and WD repeat domain containing 7 (FBXW7). Finally, orthotopic xenograft models were established to confirm the anti-glioma effect of PGA on tumour growth. We showed, for the first time, that the cytotoxic effects of PGA occurred by inducing MCL1 inhibition and FBXW7 activation by blocking ELK1-SRF complex-dependent transcription. The blockage of ELK1-mediated transcription resulted in the suppression of EGR1-BMI1, which led to the upregulation of FBXW7 expression and downregulation of MCL1. These findings suggested that PGA could be a therapeutic drug candidate for the treatment of recurrent GBM by targeting the ELK1-SRF complex.

Moschamindole induces glioma cell apoptosis by blocking Mia40-dependent mitochondrial intermembrane space assembly and oxidative respiration.

Glioblastoma multiforme (GBM) is the most frequent, lethal, and aggressive tumor of the central nervous system in adults. In this study, we found for the first time that moschamindole (MCD), a rare phenolic amide with 8/6/6/5/5 rings, is a major bioactive constituent derived from Phragmites communis Trin (Poaceae) that exhibits a potential cytotoxic effect on both TMZ-resistant GBM cell lines and xenograft models. MCD-induced intrinsic apoptosis signals and mitochondrial dysfunction were confirmed by cell cycle arrest, caspase-3/7 activation, and membrane potential depolarization. Furthermore, investigations exploring the mechanism showed that MCD specifically inhibits Mia40-mediated oxidative folding of mitochondrial intermembrane space (IMS) proteins via PCR assay and immunoblot analysis. MCD relies on its positive charge to associate with mitochondrial oxidative respiration, thus blocking energy metabolism and inducing apoptosis. Overexpression and upregulation of Mia40 were proven to reverse MCD-induced apoptosis and were correlated with the chemoresistance of GBM in vitro and in vivo, respectively. Taken together, our study demonstrates that Mia40 is a potential target of the chemoresistance of glioblastoma and suggests that MCD might be a potential agent for the individualized treatment of chemoresistant GBM based on mitochondrial metabolic characteristics and Mia40 expression.